Prolactin and growth hormone receptors are members of the cytokine receptor superfamily. Both the prolactin receptor (PRLR) and growth hormone receptor (GHR) are single chain transmembrane proteins composed of an extracellular, transmembrane and intracellular domain. The hormones prolactin (PRL) and growth hormone (GH) exert their effects at the molecular level by inducing the homodimerization of their respective receptors, initiating the activation of receptor-associated kinases and signaling cascades.
Until the last few decades, it was believed that peptide hormones circulated freely, but experimental evidence has now proven otherwise. While PRL was found to associate with serum IgG, (Walker et al. 1995 Proc. Natl. Acad. Sci. USA 92: 3278-3282) a GH-binding factor was initially identified in the serum of pregnant mice, (Peeters et al. 1977 Endocrinology 101: 1164-1183) and subsequently discovered in rabbit (Ymer et al. 1985 Mol. Cell. Endocrinol. 41: 153-161) and human sera. (Baumann et al. 1986 J. Clin. Endocrinol. Metab. 62: 134-141). With subsequent cloning of the GHR cDNA, a GH-binding protein (GHBP) was found to have amino acid sequence identity with the extracellular domain of the membrane-bound GHR. (Leung et al. 1987 Nature 330: 537-543) The GHBP is a 246 residue glycoprotein with a molecular weight of 50-60 kDA. The generation of GHRBP occurs via two separate mechanisms in mammals. In the mouse and rat, alternative splicing of a primary RNA transcript generates a truncated receptor in which the transmembrane domain is replaced by a short hydrophilic sequence (Smith et al. 3: 984-990; Baumbach et al. 1989 Genes Dev. 3: 1199-1205; Barnard et al. 1997 J. Endocrinol 153: 1-14). In other species, such as man and rabbits, a full length GHR is expressed, but GHBP is generated by proteolytic cleavage of the extracellular domain (Leung et al. 1987 Nature 330: 537-543; Trivedi et al. 1988 Endocrinology 123: 2201-2206; Sotiropoulos et al. 1993 Endocrinology 132: 1863-1865).
Although proteins in milk and serum have been found to interact with PRL, the identity of these species with the PRLR ECD had not been established. Evidence for these binding proteins in milk has been shown for man (Mercado et al. 1994 J. Clin. Endocrinol. Metab. 79: 1637-1641; Amit 1997 Mol. Cell. Endocrinol. 130: 167-180) as well as pigs, sheep and rabbits (Amit 1997 Mol. Cell. Endocrinol. 130: 167-180; Postel-Vinay et al. 1991 Proc. Natl. Acad. Sci. USA 88: 6687-6690). Even though the PRLR is highly homologous to the GHR, there was no clear evidence for a PRLP in mammalian serum.
A human prolactin-binding protein (hPRLBP) has now been identified in human serum homologous to the extracellular domain of the PRLR and a recombinant hPRLBP has been prepared. Based on its PRL binding ability, the rhPRLBP has been shown to inhibit PRL-induced proliferation of Nb2 cells.